The objective of this component is to provide three-dimensional structures of human immune system proteins relevant to the overall aims of the Program Project. Arming the immune system against pathogens is likely to require the creation of small molecule modulators of the functions of these proteins. Structures of these potential drug targets will provide a framework both for virtual screening of combinatorial libraries and for structure-guided drug design. Methods we will employ are, chiefly, high-resolution X-ray crystallography, but also include homology modeling, and, if necessary, multi-dimensional NMR. Initially our structural studies will focus on the transcription factors T-bet and XBP-1, and the multifunctional enzyme IRE-1. Specifically, we intend to express and purify both intact proteins and individual domains, and then carry out: 1. Structure determination of human T-bet (or its separately expressed domains); 2. Structure determination of the Type 2 Ser/Thr kinase and endoribonuclease domains of human IRE-1 (either separately or fused together); 3. Structure determination of the luminal ligand-binding domain of IRE-1; 4. Structure determination of the complex of human XBP-1 with a double-stranded oligonucleotide representing its target DNA sequence. As the Program Project progresses, we expect that other targets for structure determination will also appear, including upstream and downstream components of the T-bet, XBP-1 and STAT signal transduction pathways, plus proteins involves in virulence or host response to infection by Mycobacterium tuberculosis and Francisella tularensis.